Program Description/Abstract
Metabolism is the core process underlying essentially all biological functions. The goal of our research program
is to discover the mechanisms linking the metabolic state of immune cells with tissue homeostasis and
antitumor immunity, and to use these insights for development of better cancer treatments. We approach these
questions by integrating hypothesis-driven and systems immunology approaches, and our work has produced
innovation in three main areas. First, we revealed the principle of metabolic reprogramming for T cell fate, state
and tolerance. Our earlier findings in metabolic control of T cell fate and state, including T cell subset-specific
requirement of Warburg metabolism and mTOR signaling, contributed to the foundation and rapid growth of the
immunometabolism field. More recently, we identified metabolic heterogeneity in vivo that underlies T cell fate
between stemness and terminal differentiation in tumor microenvironment and inflammation, and the cycle of
metabolic quiescence and quiescence exit in immune development and function. Second, we defined
mechanisms of nutrient and immune signaling. We identified how nutrient and autophagic signals serve as
potent regulators of cellular metabolism, and how dendritic cell-derived immune and metabolic signals are
integrated by T cells. Third, we combined the traditional hypothesis-driven or ‘reductionist’ approach with
systems biology principles, including in-house development of network algorithm NetBID, pooled in vivo
CRISPR screening and systems proteomics, which led to the identification of new concepts and ‘hidden
drivers’ in immunometabolism that cannot be surmised from simpler systems. More importantly, these
approaches enabled the discovery of novel immuno-oncology targets with a clear path to clinical translation
into innovative therapeutics for pediatric cancers. Our systems immunology strategies provide functionally-
relevant discovery platforms to support future research in metabolic control of immunity and cancer.
Specifically, the future research program will address three fundamental questions in immunometabolism and
antitumor immunity, by testing the central hypothesis that immunometabolic pathways are inextricably
connected to the mechanisms of adaptive immune responses and antitumor immunity; by understanding these
connections, we gain new targets for the treatment of cancer: 1) How are nutrient signals sensed and
integrated by immune cells? 2) How can immunometabolism be rewired to improve antitumor immunity? 3)
Can we break metabolic barriers to cancer immunity and therapy, especially in therapeutically-resistant
cancers? We will focus on T cells, the cornerstone for cancer immunotherapy, to gain in-depth insights, but we
anticipate the findings can be tested and extended into other immune cells. Our experience in the application
of multidisciplinary approaches, combined with our new development and use of novel preclinical and human
disease systems for cancer immunotherapy, makes us uniquely positioned to produce fundamental discoveries
in immunometabolism and clinical translation for cancer treatments by reprogramming metabolic pathways.